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In Vivo Pharmacokinetic/Pharmacodynamic (PK/PD) Evaluation of NOSO-502, a First-In-Class Odilorhabdin Antibiotic, Against E

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In Vivo Pharmacokinetic/Pharmacodynamic (PK/PD) Evaluation of NOSO-502, a First-In-Class Odilorhabdin Antibiotic, Against E Contact Information: 1383 David R. Andes, MD University of Wisconsin Madison, WI 53705 In vivo Pharmacokinetic/Pharmacodynamic (PK/PD) Evaluation of NOSO-502, a First-in-class Odilorhabdin Phone: (608) 263-1545 Fax: (608) 263-4464 Antibiotic, against E. coli (EC) and K. pneumoniae (KPN) in the Murine Neutropenic Thigh Model Email: [email protected] M. Zhao1, A. Lepak1, D. R. Andes1 1Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI ABSTRACT METHODS (cont.) RESULTS (cont.) Background: NOSO-502 is a novel, first-in-class odilorhabdin antibiotic targeting Thigh model: Six week-old, specific pathogen free, female ICR/Swiss mice were Pharmacodynamic Index Determination: The dose-response curve and impact of dose Pharmacodynamic Target: The in vivo pharmacodynamic modelling of the PD index bacterial protein translation, with potent in vitro activity against used. Mice were rendered neutropenic by cyclophosphamide injection. Broth fractionation on the in vivo efficacy of NOSO-502 is shown for EC 25922. Doses were free drug AUC/MIC is shown for all EC and KPN isolates. The R2 is the coefficient Enterobacteriaceae including strains with MDR or CRE-phenotype. The goal of cultures of freshly plated bacteria were grown overnight to log phase. The fractionated into one, two, four or eight doses over a 24 h treatment period. Each symbol of determination and the line through the data is the best fit line based on the Hill this study was to determine the PK/PD characteristics of NOSO-502 using the 7.1 7.4 inoculum ranged from 10 – 10 CFU/mL. Thigh infections were produced by is the organism burden in one thigh. The exposure-response relationship between each equation. Also shown are the PD parameters Emax, slope of the best fit line (N) and murine thigh infection model against a diverse group of EC and KPN strains. injection of 0.1 ml of the inoculum into the thighs of isoflurane-anesthetized mice PD index is shown. The curve through the data points represent the best-fit curve based the exposure associated with 50% maximal effect (ED50). Methods: 12 strains (6 EC, 6 KPN) were utilized, including those with tetracycline 2 h before treatment with NOSO-502. Organism burden was determined by CFU on the Hill equation. The coefficient of determination (R2), Emax, 50% maximal effect or beta-lactam resistance. MICs were determined by CLSI methods. Single dose EC All isolates KPN All isolates quantitation from thigh homogenates. (ED50) and slope of the curve (N) is shown for each PD index. 4 4 murine plasma PK of NOSO-502 was determined after administration of 7.81, Emax 4.20 Emax 4.20 Pharmacodynamic Index Determination: Dose fractionation was performed in the ED 50 1.48 ED 50 1.13 N 1.26 3 N 0.75 31.25, 125 and 500 mg/kg by SC route. Dose fractionation (DF) study was used 2 3 2 neutropenic thigh model with E.coli ATCC 25922. Five total doses were R 0.88 R 0.76 4 to determine which PK/PD index was associated with efficacy. The relationship 4 2 fractionated into 3, 6, 12, and 24 hourly regimens. Each of the dose-response Emax 4.79 2 between each PK/PD indice and CFU outcome data was analyzed using the ED 50 3.04 curves was mathematically analyzed using a sigmoidal maximum effect model 3 N 0.78 CFU/thighs 3 1 CFU/thighs 1 2 10 Sigmoid Emax (Hill) model with non-linear regression. Treatment studies were (Hill equation). The correlation between efficacy and each of the three PD R 0.86 10 then performed with the remaining 11 strains. Four-fold increasing NOSO-502 indices studied was determined by nonlinear least-squares regression analysis. 2 2 0 0 2 -1 -1 doses (3.91-1000 mg/kg/6h) were administered. Treatment data and AUC/MIC CFU/thighs 1 The coefficient of determination (R ) was used to estimate the variance that CFU/thighs 1 10 Change in Log in Change Change in Log in Change was analyzed to determine AUC/MIC targets associated with net stasis and 1-log 10 could be due to regression with each of the PK/PD indices. -2 -2 0 kill for all strains. Treatment Efficacy - Pharmacodynamic Target Determination: In vivo treatment 0 -3 -3 Results: MICs ranged from 1-4 mg/L. PK ranges for doses included: Cmax 1.5-85 studies were performed with the remaining isolates. Five total doses -1 -1 0.1 1 10 100 1 10 100 1000 Change in Log in Change Q3 h Log in Change fAUC/MIC fAUC/MIC mg/L, AUC0-∞ 1.9-352 mg*h/L, T1/2 0.4-1.1 h. Regression analysis demonstrated administered SQ were fractionated into q6 hourly regimens. Four thigh Q6 h 2 2 2 -2 Q12 h -2 AUC/MIC (R 0.86) as the PK/PD driver (Cmax/MIC R 0.70, T>MIC R 0.77). infections were used for each dosing regimen. At the end of the treatment Q24 h In vivo PD target AUC/MIC for net stasis and 1-log kill for EC and KPN. Dose-dependent activity was observed against all strains, with maximal activity of -3 -3 period, organism burden was determined by CFU counts. The data was fit to a 7.81 31.25 125 500 2000 0.1 1 10 100 Stasis 1 log Kill 1-2 log killing in EC and almost 3 log killing in KPN. The 24h stasis AUC/MIC total MIC sigmoid dose-response (Hill equation) model. The dose required to produce net Total dose (mg/kg) fAUC/MIC Group Strain 24 h dose 24 h 24 h 24 h dose 24 h 24 h (mg/L) and free (non-protein bound) PK/PD targets are shown below. static effect (Static Dose, SD) and 1-log kill was calculated for each organism. (mg/kg) tAUC/MIC* fAUC/MIC* (mg/kg) tAUC/MIC fAUC/MIC Species 24h Static Dose (mg/kg) Stasis tAUC/MIC Stasis fAUC/MIC 4 25922 4 453.10 57.17 11.32 NA* The associated 24 h total and free drug targets were calculated. Emax 4.69 4 Mean 374 53 10 ED50 0.55 Emax 5.21 6042 4 214.67 19.45 3.85 496.0 64.37 12.74 N 0.77 ED50 8.65 3 2 3 N 0.91 EC Median 409 59 12 R 0.70 2 1135 4 474.76 60.81 12.04 NA R 0.77 SD 182 32 6.3 681 2 364.98 84.78 16.79 NA RESULTS 2 2 Mean 81 21 4.2 EC 1-894-1 4 615.97 84.49 16.73 NA CFU/thighs 1 CFU/thighs 1 10 1-741-1 4 119.75 9.63 1.91 172.6 15.10 2.99 KPN Median 56 9.1 1.8 10 In vitro susceptibility testing for NOSO-502 against study organisms: SD 56 24 4.7 0 0 Mean 373.87 52.72 10.44 Median 409.04 58.99 11.68 Conclusions: NOSO-502 demonstrated in vivo potency against a diverse group of MIC MIC -1 -1 Std Dev 181.70 31.89 6.32 Change in Log in Change Isolate (mg/L) Comment Isolate (mg/L) Comment Log in Change EC and KPN strains including those with resistance to tetracycline and beta- 43816 2 55.78 6.63 1.31 276.00 54.93 10.88 EC 25922 4 ATCC KPN 43816 2 ATCC -2 -2 lactams. The PK/PD index predictive of efficacy is AUC/MIC. Stasis 24 h BAA 2146 1 48.84 11.64 2.30 90.78 26.54 5.25 EC 6042 4 TEM-10 KPN BAA 2146 1 NDM-1 AUC/MIC targets were ≤10 for both KPN and EC. This data should be useful for -3 -3 216 2 55.95 6.65 1.32 446.28 112.05 22.19 EC 1135 4 Tet(M), ESBL KPN 216 2 0.01 0.1 1 10 0 20 40 60 80 100 developing dosing regimens for clinical study of NOSO-502. 4105 2 31.53 3.79 0.75 77.72 10.57 2.09 EC 681 2 ESBL KPN 4105 2 TEM 26, SHV-1 fCmax/MIC %T/MIC KPN 4110 1 111.67 35.18 6.97 NA EC 1-894-1 4 TET-RES KPN 4110 1 TEM 10, SHV-1 81-1260A 1 181.56 64.09 12.69 474.71 243.19 48.15 EC 1-741-1 4 TET-RES KPN 81-1260A 1 CTX-M3, AmpC BACKGROUND Mean 80.89 21.33 4.22 273.10 89.45 17.71 Treatment Efficacy: In vivo dose-response curves for NOSO-502 against 6 EC and 6 KPN • Novel agents for Gram-negative infections, especially those caused by drug- Median 55.87 9.14 1.81 276.00 54.93 10.88 Pharmacokinetics: Plasma PK of NOSO-502 and select PK parameters including isolates in the neutropenic thigh model. Each symbol represents the mean and standard Std Dev 56.21 23.89 4.73 188.45 94.23 18.66 resistant Enterobacteriaceae, are needed. AUC0-∞, Cmax, and elimination half-life (T1/2). Protein binding was 80.2%. The results deviation from six thighs. Five total drug doses were fractionated into an every 6 hourly tAUC/MIC*, total drug AUC/MIC; fAUC/MIC*, free drug AUC/MIC; NA*, not achieved. • NOSO-502 belongs to a novel class of peptide antibiotics, odilorhabdins from these studies were used to estimate pharmacokinetic values at dose levels for regimen.
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